The goal of this project is to understand the role of dysregulated lipid metabolism in development of HIV-associated neurocognitive disorders (HAND) in older HIV patients on long-term antiretroviral therapy (ART), and how these processes are influenced by hepatic dysfunction, chronic inflammation, and aging. Long-term ART is associated with metabolic abnormalities and increased risk of diseases typically associated with aging including cardiovascular, liver, kidney, bone, and neurological disorders. Mild forms of HAND affect 30-50% of HIV patients on long-term ART, and are more frequent in HIV patients over age 50. In preliminary studies, we performed untargeted metabolite profiling and identified 126 metabolites altered in plasma of HIV patients on suppressive ART, of which 47% were lipids. Lipid alterations correlated with markers of hepatic and mitochondrial dysfunction, and represented specific classes distinct from traditional markers. Some altered lipids belonging to specific classes correlated with cognitive impairment, while others correlated primarily with deficits in motor or executive function, based on analyses using normalized neurocognitive test scores (T scores). We hypothesize that dysregulated lipid metabolism, a consequence of hepatic dysfunction induced by HIV or HIV/HCV infection, chronic inflammation, hepatotoxicity of some ART drugs, and other factors, promotes white matter abnormalities and cognitive decline in older adults with HIV infection. Aging modifies these processes through age-related alterations in lipid metabolism, mitochondrial function, autophagy, and inflammatory responses. To investigate this hypothesis, we will use systems biology approaches to analyze large-scale clinical, biological, metabolomics, and transcriptomics datasets from HIV patients age 50 and older on long-term ART with different clinical outcomes. Integrative data analysis and targeted experimentation will be used to computationally build models of relevant networks and pathways. These studies will create a new conceptual framework for understanding metabolic pathways driving HAND in older adults on long-term ART, which may provide important insights into the biology of cognitive and neurobehavioral disorders in other aging populations and developing new therapies. PUBLIC HEALTH RELEVANCE: This project will use large-scale clinical and biological datasets from well-characterized study cohorts, computational modeling, and systems biology approaches to identify altered metabolic pathways involved in the development of cognitive dysfunction in older adults with HIV infection on long-term antiretroviral therapies. These studies will create a new conceptual framework for understanding metabolic pathways driving HIV- associated cognitive impairment in older adults on long-term ART, which may provide insights into the biology of cognitive and neurobehavioral disorders in other aging populations and developing new therapies.